This invention relates to the use of adenosine 5'-diphosphate (ADP) and/or adenosine 5'-triphosphate (ATP) for selective inhibition of growth and subsequent killing of malignant cells, e.g., human malignant cells, thereby utilizing a normal metabolite for inhibiting, e.g., human tumor cell growth.
It is known to use antimetabolites (e.g., cytotoxic nucleosides or bases) such as purines and pyrimidines as antineoplastic drugs. However, such antimetabolites are taken up by both normal and tumor cells, and therefore not only can inhibit the growth of tumor cells, but also growth of normal cells.
U.S. Pat. No. 4,291,024 to Turcotte discloses a process for the preparation of liponucleotide analogs of nucleosides or bases having known cytotoxic activity (e.g., 1-.beta.-D-arabinofuranosyl-cytosine, known as Ara-C). This patent discloses that these liponucleotide analogs of nucleosides provide a means for delivering cytotoxic nucleosides into the tumor cells. Once inside the cells, the cytotoxic nucleoside can be released in a phosphorylated form, thus circumventing the dependency upon kinase activity on the nucleoside itself. This is beneficial since the cytotoxic nucleosides or bases exert their anti-proliferative activities via the nucleoside triphosphate form. The objects stated in U.S. Pat. No. 4,291,024 do not mention delivery of normal cellular metabolites (e.g., ADP or ATP) into tumor cells via the liponucleotide analog; however, the liponucleotide analog of ADP falls within the broad disclosure of this U.S. patent. In any event, the liponucleotide analog disclosed by Turcotte enter the cancer cell via the process of lysosomo-tropism or related membrane phenomena; as such, these analogs can also enter normal non-cancerous cells (e.g., bone marrow, lymph node or intestinal epithelium cells), resulting in disruption of the normal cycling cell metabolism.
ATP is a known vasodilator that may cause circulatory changes in humans and experimental animals. See, e.g., Davies, et al., "Circulatory and Respiratory Effects of Adenosine Triphosphate in Man", in Circulation 3:543-550 (April 1951); Duff, et al., "A Quantitative Study of the Response to Adenosine Triphosphate of the Blood Vessels of the Human Hand and Forearm, in J. Physiol. 125:581-589 (1954); Rowe, et al., "The Systemic and Coronary Hemodynamic Effects of Adenosine Triphosphate and Adenosine", in American Heart J. 64:228-234 (1962). Moreover, cellular pools of acid-soluble nucleotides, especially ADP and ATP, have been previously shown by Rapaport and collaborators to act in the regulation of DNA replication and growth of mammalian cells. See, e.g., Rapaport, et al., "Incorporation of Adenosine into ATP:Formation of Compartmentalized ATP", in Proc. Natl. Acad. Sci. USA, Vol. 73, No. 9:3122-3125 (September 1976); Rapaport, et al., "Increased Incorporation of Adenosine into Adenine Nucleotide Pools in Serum-Deprived Mammalian Cells", in Proc. Natl. Acad. Sci. USA, Vol. 75, No. 3:1145-1147 (March 1978); Rapaport, et al., "Elevated Nuclear ATP Pools and ATP/ADP Ratios Mediate Adenosine Toxicity in Fibroblasts", In Regulation of Macromolecular Synthesis by Low Molecular Weight Mediators, Acadamic Press, 1979, pp. 223-231; Rapaport, et al., "Regulation of DNA Replication in S Phase Nuclei by ATP and ADP Pools", in Proc. Natl. Acad. Sci. USA, Vol. 76, No. 4:1643-1647 (April 1979); Rapaport, et al., "Selective High Metabolic Lability of Uridine, Guanosine and Cytosine Triphosphate in Response to Glucose Deprivation and Refeeding of Untransformed and Polyoma Virus-transformed Hamster Fibroblasts", in J. Cell. Physiol., Vol. 101, No. 2:229-236 (November 1979); Rapaport, et al., "Selective High Metabolic Liability of Uridine Triphosphate in Response to Glucosamine Feeding of Untransformed and Polyoma Virus-transformed Hamster Fibroblasts", in J. Cell. Physiol., 104:253-259 (1980); Rapaport, "Compartmentalized ATP Pools Produced from Adenosine Are Nuclear Pools", in J. Cell. Physiol., 105:267-274 (1980); and Rapaport, et al., "Retinoic Acid-Promoted Expansion of Tofal Cellular ATP Pools in 3T3 Cells Can Mediate its Stimulatory and Growth Inhibitory Effects" in J. Cell. Physiol., 110:318-322 (1982).
However, these references showing use of ADP and ATP as regulators of DNA replication and growth of mammalian cells do not disclose that the materials, or a process of using such materials, selectively attack malignant cells, e.g., human malignant cells, and not attack normal cells, leading to the arrest of growth and killing of said malignant cells while causing sustantially no arrest of growth or killing of normal cells.